Synthesis of benzoprostacyclins using palladium catalysis

ABSTRACT

A method is provided for preparing benzoprostacyclins by the palladium-catalyzed tandem alkene insertion into a 1,4-bisoxy-substituted cyclopent-2-ene intermediate.

BACKGROUND OF THE INVENTION

Prostacyclin (I, PGI₂), first discovered in 1976, is one of the mostpotent natural inhibitors of blood platelet aggregation. (See S. Moncadoet al., Nature, 263, 663 (1976) and R. Johnson et al., Prostaglandins,12, 915 (1976)). Unfortunately, its low metabolic stability due to enolether hydrolysis greatly diminished its pharmacological utility. Majorinterest of late has focused on the synthesis of more stable analogs,such as the benzoprostacyclins Ia-c, described by K. Ohno et al. in U.S.Pat. No. 4,301,164. ##STR1## These compounds similarly exhibitsubstantial inhibition of platelet aggregation.

Present synthetic approaches to the benzoprostacyclins are very lengthyand rather inefficient. For example, the synthesis of compound Ia asreported by H. Nagase et al., Tetrahedron Lett., 31, 4493 (1990)requires 23 steps. As reported by K. Ohno et al. in U.S. Pat. No.4,474,802, the synthesis of the C₁ -methyl ester of Ib requires at least17 steps.

Therefore, a need exists for efficient methods to synthesizebenzoprostacyclins.

SUMMARY OF THE INVENTION

The present invention provides a method for the synthesis ofbenzoprostacyclins of general formula II. ##STR2## wherein R¹ is apharmaceutically acceptable cation, H or (C₁ -C₁₂)alkyl, preferably (C₁-C₄)alkyl; R² is H, (C₁ -C₁₂)-alkyl, (C₂ -C₁₀)acyl or (C₇ -C₁₃)aroyl; R⁸is H or (C₁ -C₁₂)alkyl, and R⁹ is OR³ wherein R³ is H, (C₁ -C₁₂)alkyl,(C₂ -C₁₀)acyl, or (C₇ -C₁₃)aroyl; or R⁸ and R⁹ taken together are keto;R⁴ is H, F, methyl or ethyl; R⁵ is (C₁ -C₅)alkyl; A is --CH₂ --,--O--CH₂ --, --CH₂ --CH₂ -- or --CH═CH--, and B is --(CH₂)_(n) --Z--wherein n is 0-4 and Z is --CH₂ --CH₂ --, --CH═CH-- or --C.tbd.C--.

In compound II, the bonds at cyclopentane ring positions 8, 9 11 and 12,individually are in either the alpha (extending below the plane of thecyclopentane ring, indicated by a broken line) or beta (extending abovethe plane of the cyclopentane ring, indicated by a wedged line)configuration, with the "natural" configuration shown for 1. Theall-alpha or all-beta configurations are readily prepared by the presentmethod. The configuration at C₁₅ may be either (R) or (S). Preferably,the C₈ and C₉ cyclopentane ring bonds are both alpha (the "natural"configuration) or both beta.

Two novel compounds which can be prepared in accord with the presentmethod wherein R¹, A, R², R³, R⁴, B and R⁵ are as described hereinabove,are depicted below (IIa, IIb). ##STR3## Representative compounds offormula II, wherein A=--CH₂ --CH₂ --, R² =R³ =R⁴ =H, B=--(CH₂)₃ -- andR⁵ =CH₃, which were prepared in accord with the present method arelisted in Table I, below.

                  TABLE I                                                         ______________________________________                                        Benzoprostacyclin Analogs                                                               Bond Orientation                                                    Compound No.                                                                              C.sub.8 C.sub.9                                                                             C.sub.12                                                                             C.sub.13                                                                           C.sub.15 --OH                           ______________________________________                                        16 (R.sup.1 = Et)                                                                         α α                                                                             α                                                                              α                                                                            C.sub.15 ═O                         17 (R.sup.1 = Et)                                                                         α α                                                                             α                                                                              α                                                                            α                                 18 (R.sup.1 = Et)                                                                         α α                                                                             α                                                                              α                                                                            β                                  17 (R.sup.1 = H)                                                                          α α                                                                             α                                                                              α                                                                            α                                 18 (R.sup.1 = H)                                                                          α α                                                                             α                                                                              α                                                                            β                                  19 (R.sup.1 = Et)                                                                         β  β                                                                              β β                                                                             α                                 ______________________________________                                    

The present invention is also directed to intermediate III, which isemployed in the present synthetic method: ##STR4## wherein R¹ is (C₁-C₁₂) alkyl and A and R² are as defined above. Preferably, the1,4-cyclopentenyloxy bonds are both alpha, R² is H, and R¹ is (C₁-C₄)alkyl.

As used herein, the term "alkyl" includes branched or straight-chainalkyl groups, or (C₃ -C₁₂)cycloalkyl, preferably (C₃ -C₆)cycloalkyl.Aroyl is preferably benzoyl or naphthoyl, wherein the aryl ring iseither unsubstituted or is substituted with 1-4 (C₁ -C₄)alkyl or 1-4 (C₁-C₄)alkoxy groups. The preferred acyl is acetyl. Preferably A and B aremethylene (--CH₂ --) or ethylene (--CH₂ --CH₂ --). Preferredpharmaceutically-acceptable cations are alkali metal salts, NH₄ ⁺, orthe carboxylic acid addition salts of non-toxic amines.

In accord with the present method, a compound of the formula III,wherein R² is as defined above, and preferably is H; R¹ is as definedabove, and preferably is (C₁ -C₁₂)alkyl and A is as defined above, andpreferably is --CH₂ -- or --CH₂ --CH₂ --, is reacted with a compound ofthe formula IV:

    R.sup.7 --CH═CH--C(R.sup.8)(R.sup.9)--CH(R.sup.4)--B--R.sup.5 IV

wherein R⁷ is H, tris(C₁ -C₄)alkylSn or (phenyl)₃ Sn; R⁸ is H or (C₁-C₁₂)alkyl and R⁹ is OR³ ; or R⁸ and R⁹ taken together are keto; and R³,R⁴, B and R⁵ are as described hereinabove; in the presence of acatalytic amount of palladium(O)(Pd(O)), and an organic base to directlyyield the corresponding compound of formula II. When R⁷ is trialkylSn-or triphenylSn, preferably R⁸ is H and R⁹ is OH. Preferably, thereaction is carried out in the presence of an organic amine, preferablyi-Pr₂ NEt, most preferably also in the presence of a source of chlorideion (Cl⁻), such as an alkali metal chloride or a tetraalkylammoniumchloride, such as n-Bu₄ NCl.

When R⁸ and R⁹ together are keto, the keto group can then be reduced tothe corresponding C₁₅ -hydroxy group by methods known to the art.Optionally, in either case, the C₁ -ester can then be saponified ifnecessary, to yield compounds of formula II wherein R¹ is H, and the CO₂H group can also be converted into a pharmaceutically-acceptablecarboxylate salt.

The moiety --CH═CH-- may be cis or trans. It is preferably trans incompound IV, and cis in moieties A and B in compounds II or III.

DETAILED DESCRIPTION OF THE INVENTION

The preparation of a preferred embodiment of intermediate III issummarized in Scheme 1. ##STR5## Steps (a)-(g) are summarized in TableII below, wherein the numbers preceding the reactants are mole ratios: 1mole of 1-8, unless otherwise noted.

                  TABLE II                                                        ______________________________________                                        Synthesis of Compound 9                                                       Step      Reactants         Yield                                             ______________________________________                                        a         1.2 allyl bromide,                                                                              94%                                                         1.2 K.sub.2 CO.sub.3, acetone                                       b         0.8 MeAlCl.sub.2, -20° C.                                                                70%                                               c         t-butyldimethylsilyl                                                                            90%                                                         chloride, imidazole                                                 d         ozone, -78° C./Me.sub.2 S                                                                83%                                               e         Ph.sub.3 P═CHCO.sub.2 Et                                                                    83%                                               f         H.sub.2, cat. PtO.sub.2                                                                         90%                                               g         n-Bu.sub.4 NF     94%                                               h         1,5-cyclopentadiene                                                                             72%                                                         monoepoxide, 2% Pd(PPh.sub.3).sub.4,                                          THF                                                                 ______________________________________                                    

The requisite regio- and stereochemistry is efficiently introduced bythe palladium-catalyzed opening of a vinylic epoxide. See, D. R.Deardorff et al., Tetrahedron Lett., 26, 5615 (1984).

The reaction of 9 with 1-octen-3-one, n-Bu₄ NCl and i-Pr₂ NEt, in a moleratio to 9 of 10:1.1:2.5, respectively, proceeded in 43% yield in thepresence of 5% Pd(OAc)₂ at 50° C. in DMF to give compound 16, as shownin Scheme 2, below. ##STR6##

Mechanistically, this process is believed to involve (1) reduction ofPd(OAc)₂ to Pd(O), (2) oxidative addition of the aryl iodide of 9 toPd(O) (without apparent competitive displacement of the aryloxy group toform a π-allylpalladium intermediate which would deactivate thecatalyst), (3) intermolecular syn insertion of the cyclopentene doublebond to form a bicyclic alkylpalladium intermediate which is blockedfrom syn palladium β-hydride elimination by the hydroxy group, (4) enoneinsertion into the carbon-palladium bond, and finally (5) palladiumβ-hydride elimination to the enone 16 (subsequent palladium hydridedecomposition of Pd(O) regenerates the catalyst and completes thecatalytic cycle).

(S)-BINAL-H reduction of enone 16 in accord with the procedure of R.Noyori et al., J. Amer. Chem, Soc., 106, 6717 (1984), was unselective,affording an easily separable 1:1 mixture of diastereomers in 50% yield,in accord with Scheme 3, below. ##STR7## Saponification of esters 17(R=Et) and 18 (R=et) afforded the corresponding carboxylic acids 17(R=H) and 18 (R=H) in 83% and 92% yields, respectively.

These stereochemical difficulties can be overcome in part by replacingthe 1-alken-3-one in Scheme 2 with chiral vinylic stannane 14 as shownin Scheme 4. A separable mixture of diastereomers 17 (R=Et) and 19(R=Et) was obtained in 30% overall yield. ##STR8##

SYNTHETIC METHODOLOGY

The compound which is the source of the Pd(O) catalyst is generallyemployed in an amount of about 0.001-20 mol-%, preferably 0.1-10 mol-%,based on the compound of formula III. Useful catalysts include, forexample, bis(dibenzylideneacetone)palladium (O),bis-(isonitrile)palladium (O), bis-(cyclohexylisonitrile)palladium(O),bis-(isopropylisonitrile)palladium(O),bis-(tert.-butylisonitrile)-palladium(O),bis-(p-tolylsionitrile)palladium(O), bis-(phenylisonitrile)palladium(O), and bis-(p-methoxyphenylisonitrile)palladium (O).

Other Pd-containing compounds, e.g., Pd(II) compounds, can also be usedin the present method under conditions wherein Pd(O) is generated. Theseinclude PdCl₂, palladium(II) carboxylate salts, such as Pd(OAc)₂, PdBr₂,Pd(CN)₂, Pd(NO₃)₂ and the like. Other Pd catalysts which can be used inthe present method include those disclosed in Blaser et al. (U.S. Pat.No. 4,335,054) at Col. 6, line 5 to Col. 7, line 3.

Bases used in the present process can be inorganic or organic bases,which are adequately soluble in the reaction medium. Representativebases are disclosed at Col. 7, lines 8-65 of the Blaser et al. patent.Inorganic bases for use in the present process include Na₂ CO₃, KHCO₃,Li₂ CO₃, and NaHCO₃. Useful organic bases include trialkylamines, suchas diisopropyl(ethyl)amine. Preferably, organic bases are used. Thepreferred mole ratio of the base to the compound of formula III is about2-3:1.

A source of halide, such as chloride ion, is also preferably used in thepresent process, in an amount effective to promote the reaction andincrease the yield. Organic chloride sources such astetra(alkyl)ammonium chlorides, wherein the alkyls can each be about (C₂-C₁₂)-alkyl, are preferred, i.e., (n-Bu)₄ NCl. Alkali metal halides suchas MX, wherein M is Li, Na, or K and X is Cl, Br or I, can also be used.Preferred in the present method are a mixture of diisopropyl(ethyl)amineand tetra-n-butylammonium chloride (n-Bu₄ NCl). The halide source ispreferably used in only a slight excess over the compound of formulaIII, (1.1-1.5 equivalents).

In carrying out the synthesis of the compound of formula II, the aryliodide III is preferably combined with an excess of compound IV, e.g.,preferable in a mole ratio of III:IV of about 1:1.25-20, in a suitableorganic solvent. The reaction mixture is preferably stirred at about20°-75° C. for about 5-48 hr. under an inert atmosphere. The crudeproduct is extracted, i.e., into ethyl acetate and can be purified bychromatography.

Useful organic solvents include tetrahydrofuran (THF), ethers, glycolethers, dimethylsulfoxide, dimethylformamide (DMF), acetonitrile,acetamide, dimethylacetamide, and hexamethylphosphoramide.

Compounds of formula IV, wherein R⁷ =H and R⁸ and R⁹ taken together areketo, e.g., vinyl(alkyl or alkylene)ketones can be readily prepared,e.g., by the reaction of vinylmagnesium bromide with acid chlorides ofthe general formula R⁵ -B-(R⁴)CH-COCl, wherein R⁵, B and R⁴ are asdescribed above. Compounds of formula IV, wherein R⁷ is atrialkylstannyl group, R⁸ is H and R⁹ is OR³ can be prepared asdisclosed by J. K. Stille, in Angew. Chem. Int. Ed. Engl., 25, 508(1986), M. Ochiai et al., Tet. Letters, 24, 4025 (1983), and by G. Kecket al., J. Org. Chem., 52, 2958 (1987). For example tri-n-butyltinhydride can be reacted with a protected 3-hydroxy-1-alkyne as disclosedin U.S. Pat. No. 4,230,879.

The reduction of C₁₅ -keto-benzoprostacyclins to yield compounds offormula II, wherein R³ =H can be accomplished with borohydride reducingagents such as zinc borohydride or sodium borohydride, or with chiralreducing agents such as lithium aluminum hydride/α, α'-binaphthol((S)-BINAL-H), as described in detail in the working Examples, below andin Aldrichimica Acta, 6, 14 (1983). The free C₁₁ --OH or C₁₅ --OH groupscan then be acylated or aroylated by conventional methodologies, e.g.,via reaction with anhydrides or acid chlorides in the presence of anorganic base. Compounds of formula II wherein R¹ is alkyl can beconverted into the corresponding carboyxlic acids by saponification withalkali metal hydroxides in alcoholic solvents followed by neutralizationof the reaction mixture. Pharmaceutically-acceptable cations (R¹)include alkali metal salts and the amine salts disclosed in K. Ohno etal. (U.S. Pat. No. 4,474,802), which is incorporated by referenceherein.

The reaction methodology employed to prepare compound 9, as outlined inScheme 1, can be readily modified to prepare other aryl iodides ofgeneral formula III, e.g., by the use of aldehydes of varying chainlength in step (e). Compound III wherein A is CH=CH and R² is H isreadily prepared by deprotecting compound 6, e.g., via step (g).

BIOASSAYS

The compounds prepared by the present method exhibit potent plateletaggregation inhibiting activity and blood pressure decreasing activityby vasodilation. The efficacy of the compound to inhibit plateletaggregation is examined according to Born's method (Nature, 194, 927(1962)). The blood is collected from humans or anesthetized rabbits. Theblood is anti-coagulated with a 3.8% aqueous solution of sodium citratein an amount of a tenth volume of the blood and centrifuged for 10minutes at 200×g to obtain platelet rich plasma. After pretreatment ofthe platelet rich plasma with the benzoprostacyclin, aggregation ismeasured by aggregometer with arachidonic acid,adenosine-2-phosphate(ADP) or collagen as the aggregation inducer. It isshown that compounds 16 (R=Et), 17 (R=Et), 18 (R=Et), 17 (R=H), 18(R=H), and 19 (R=Et) exhibit potent inhibitory activity.

To examine the efficacy of a benzoprostacyclin to reduce blood pressure,the blood pressure of the carotid artery of rats under pentobarbitalanesthesia is measured. The compounds listed above are injected into thevein through an indwelling catheter. These compounds exhibitsubstantially the same activity as prostaglandin E₁ at the same dose of0.05 to 100 μg/kg and have a longer duration of action thanprostaglandin E₁.

An anti-thrombotic agent containing any of these benzoprostacyclins asthe active component may be applied to prevent clotting inextracorporeal circulation, treatment of a disturbance of peripheralcirculation such as Buerger's disease and Raynaud's disease, preventionand treatment of myocardial infarction, angina pectoris and cerebralinfarction, prevention of TIA, treatment of diabetic thrombosis andprevention and treatment of arteriosclerosis.

For the treatment of Buerger's disease, the pharmacologically effectiveintravenous dose of a compound of the invention is 0.001 to 100μg/kg/min. In case of using the compound as an anti-thrombotic agent,0.001 to 50 mg of the compound is orally administered to a patient oneto three times a day, and in case of using the compound as a bloodpressure-reducing agent, 0.01 to 50 mg of the compound is orallyadministered to a patient one to three times a day.

The benzoprostacyclins can be orally administered as a form of a solidsubstance containing excipients such as starch, lactose, and sucrose, orcan be parenterally administered in a form of a sterilized aqueoussolution. Such a solution may contain another solute, for instance,glucose or sodium chloride in an amount sufficient to make the solutionisotonic. Various preparations for oral administration, injections,infusions, eye drops and suppositories can be prepared.

The invention will be further described by reference to the followingdetailed examples.

EXAMPLE 1 Preparation of Compound 2

A solution of o-iodophenol (6.6 g, 30 mmol), allyl bromide (4.0 g, 33mmol) and potassium carbonate (4.6 g, 3.3 mmol) in 7.5 ml of acetone wasrefluxed for 8 hr. The reaction mixture was diluted with 40 ml of water,and extracted with ether (2×25 ml). The organic phase was washed withbrine (25 ml), and then dried over MgSO₄. Concentration, followed byflash chromatography, gave compound 2 as a colorless oil: 6.8 g, 94%yield, ¹ H NMR (CDCl₃) δ 7.77 (dd, J=17.4 and 10.5 and 7.8 Hz, 1.5 Hz, 1H, Ar), 7.27 (dt, J=1.8 and 7.8 Hz, 1 H, Ar), 6.80 (dd, J=7.8 and 1.2Hz, 1 H, Ar), 6.70 (dt, J=7.8 and 1.2 Hz, 1 H, Ar), 6.06 (ddt, J=17.4and 10.5 and 7.8 Hz, 1 H, HC=C), 5.52 (dd, J=17.4 and 1.8 Hz, 1 H,HC=C), 5.31 (dd, J=10.5 and 1.2 Hz, 1 H, HC=C), 4.59 (dt, J=4.8 and 1.5Hz, 2 H, CH₂); ¹³ C NMR (CDCl₃) δ 157.09, 139.51, 132.57, 129.35,122.66, 117.59, 112.58, 86.72, 69.68; IR (neat) 1582, 1477 cm⁻¹.

EXAMPLE 2 Preparation of 6-allyl-2-iodophenol 3

To a solution of compound 2 (7.0 g, 27 mmol) in 130 ml of hexane wasadded MeAlCl₂ (Aldrich, 1.0 M in hexane, 22 ml 22 mmol) dropwise at -20°C. After the reaction mixture was stirred for 2 hr. at -20° C. undernitrogen, the reaction was quenched by adding water (40 ml) and themixture slowly warmed to room temperature with swirling. Ethyl acetate(30 ml) was added to the reaction mixture, then stirring was continuedfor 5 min. After separating phases, the organic phase was washed withwater (30 ml) and brine (30 ml), then dried and concentrated. Theresidue was purified by flash chromatography with 15:1 hexane/EtOAc togive product 3: 4.9 g, 70% yield; R_(f) =0.38 (20:1 hexane/EtOAc); ¹ HNMR (CDCl₃) δ 7.51 (dd, J=1.2 and 7.8 Hz, 1 H, Ar), 7.07 (d, J=7.8 Hz, 1H, Ar), 6.62 (t, J=7.8 Hz, 1 H, Ar), 5.98 (ddt, J=17.4 and 9.6 and 6.6Hz, 1 H, HC=C), 5.37 (s, 1 H, OH), 5.12 (m, 1 H, CH=C), 5.07 (m, 1 H,CH=C), 3.43 (d, J=6.6 Hz, 2 H, CH₂); ¹³ C NMR (CDCl₃) δ 152.60, 136.33,136.01, 130.73, 126.81, 122.42, 116.22, 86.41, 35.56; IR (neat) 3487(OH), 1593, 1234 cm⁻¹ ; LRMS m/z (relative intensity) 51.1 (34), 77.1(47), 105.1 (58), 118.1 (41), 133.1 (42), 260.0 (M⁺, 100).

EXAMPLE 3 Preparation of Compound 4

To a solution of compound 3 (4.9 g, 18.7 mmol) and imidazole (3.2 g,47.1 mmol) in 20 ml of DMF was added t-butyldimethylsilyl chloride (3.1g, 20.5 mmol) dissolved in 15 mmol of DMF at room temperature undernitrogen. After the mixture was stirred for 12 hr. at room temperature,it was extracted with hexane (50 ml×8). The hexane phase wasconcentrated and then flash chromatographed to give compound 4: 6.3 g,90% yield; R_(f) =0.52 (hexane); ¹ H NMR (CDCl₃) δ 7.63 (dd, J=7.8 and1.8 Hz, 1 H, Ar), 7.11 (dd J=7.8 and 1.8 HZ, 1 H, Ar), 6.66 (t, J =7.8Hz, 1 H, Ar), 5.86 (ddt, J=17.4 and 9.6 and 6.6 Hz, 1 H, C=CHCH₂), 5.08(m, 2 H, H₂ C=C), 3.39 (d, J=6.9 Hz, 2 H, CH₂), 1.06 (s, 9 H, t-BuSi),0.331 (s, 6 H, SiMe₂).

EXAMPLE 4 Preparation of Compound 5

Ozone was passed through a solution of compound 4 (722 mg, 1.9 mmol) in19 ml of methanol at -78° C. until the deep blue color persisted (about15 min.). The reaction was flushed with nitrogen gas and 8 ml of CH₃SCH₃ was added at -78° C. The reaction mixture was then allowed to stirfor 30 min. at -78° C., for 1 hr. at 0° C and for another 30 min. atroom temperature. The methanol solvent was evaporated under reducedpressure, and 60 ml of ether was then added to the residue. After themixture was washed with water (10 ml) and brine (20 ml×2), it was driedand concentrated. Flash chromatography gave product 5: 638 mg, 83%yield; R_(f) =0.63 (3:1 hexane/EtOAc); ¹ H NMR (CDCl₃) δ 9.63 (t, J=2.1Hz, 1 H, CHO), 7.74 (dd, J=8.1 and 1.5 Hz, 1 H, Ar), 7.09 (dd, J=7.5 and1.5 Hz, 1 H, Ar), 6.72 (t, J=7.5 Hz, 1 H, Ar), 3.68 (d, J=2.1 Hz, 2 H,CH₂), 1.05 (s, 9 H, t-BuSi), 0.32 (s, 6 H, SiMe₂); ¹³ C NMR (CDCl₃) δ199.34, 153.92, 139.70, 131.54, 124.26, 123.81, 91.23, 46.16, 26.37,18.85, -1.52.

EXAMPLE 5 Preparation of Compound 6

To a solution of (carboxymethylene)triphenylphosphorane (Aldrich, 3.88g, 11.5 mmol) dissolved in 30 ml of CH₂ Cl₂ was added dropwise at roomtemperature aldehyde 5 (3.57 g, 9.3 mmol) dissolved in 14 ml of CH₂ Cl₂.After the reaction was stirred for 12 hr. at room temperature, it wasconcentrated in vacuo and purified by flash chromatography with 5:1hexane/EtOAc to give ester 6: 3.52 g, 83% yield; R_(f) =0.46 (5:1hexane/EtOAc); ¹ H NMR (CDCl₃) δ 7.67 (dd, J=7.8 and 1.5 Hz, 1 H, Ar),7.05 (dd, J=7.5 and 1.5 Hz, 1 H, Ar), 6.99 (dt, J=15.6 and 6.6 Hz, 1 H,HC=C) 6.66 (t, J=7.5 Hz, 1 H, Ar), 5.80 (d, J=15.6 Hz, 1 H, CH=C), 4.18(q, J=7.2 Hz, 2 H, OCH₂), 3.53 (dd, J=6.9 and 1.5 Hz, 2 H, CH₂), 1.27(t, J=7.2 Hz, 3 H CH₃), 1.05 (s, 9 H, t-BuSi), 0.32 (s, 6 H, Me₂ Si); ¹³C NMR (CDCl₃) δ 166.32, 153.31, 146.18, 138.75, 130.60, 129.52, 123.61,122.93, 91.09, 60.36, 33.94, 26.42, 18.94, 14.32, -1.49.

EXAMPLE 6 Preparation of Compound 7

To a three neck flask equipped with a hydrogen-filled gas balloon wereadded α,β-unsaturated ester 6 (619 mg, 1.36 mmol), ethanol (20 ml), 2 Naqueous HCl (0.4 ml) and PtO₂ (Aldrich, 60 mg). The reaction was flushedwith hydrogen gas using an aspirator, and then stirred for 1 hr. at roomtemperature under the hydrogen balloon pressure. After the reaction wasneutralized with 3 N aqueous NaOH (0.27 ml), it was poured into 100 mlof ethyl acetate (EtOAc). The solution was washed with brine (50 ml, 25ml) and concentrated in vacuo. The residue was purified by flashchromatography to give compound 7: 562 mg, 90% yield; R_(f) =0.52 (7:1hexane/EtOAc); ¹ H NMR (CDCl₃) δ7.62 (dd, J=7.8 and 1.5 Hz, 1 H, Ar),7.10 (dd, J=7.8 and 1.5 Hz, 1 H, Ar), 6.64 (t, J=7.8 Hz, 1 H, Ar), 4.11(q, J=7.2 Hz, 2 H, OCH₂), 2.66 (t, J=7.8 Hz, 2 H, CH₂), 2.27 (t, J=7.5Hz, 2 H, CH₂), 1.88 (m, 2 H, CH₂), 1.25 (t, J=7.2 Hz, 3 H, CH₂), 1.04(s, 9 H, t-BuSi), 0.32 (s, 6 H, SiMe₂).

EXAMPLE 7 Preparation of Compound 8

To a solution of compound 7 (2.85 g, 6.2 mmol) in 60 ml of THF at -78°C. was added n-Bu₄ NF (Aldrich, 1.0 M in THF, 6.2 ml, 6.2 mmol). Thereaction mixture was stirred for 1 hr. at -78° C., then allowed to warmto 0° C., and quenched by adding water (10 ml). The mixture was pouredinto 50 ml of ethyl acetate, and washed with water (25 ml) and brine (20ml). The organic phase was dried and concentrated. The residue waspurified by flash chromatography with 4:1 hexane/EtOAc to give compound8: 2.02 g, 94% yield; R_(f) =0.37 (5:1 hexane/EtOAc); ¹ H NMR (CDCl₃) δ7.53 (dd, J=7.8 and 1.2 Hz, 1 H, Ar), 7.05 (dd, J=7.8 and 1.2 Hz, 1 H,Ar), 6.58 (t, J=7.8 Hz, 1 H, Ar), 6.18 (s, 1 H, OH), 4.15 (q, J=7.2 Hz,2 H, CH₂), 2.69 (t, J=7.2 Hz, 2 H, CH₂), 2.36 (t, J =7.2 Hz, 2 H, CH₂),1.91 (m, 2 H, CH₂), 1.27 (t, J=7.2 Hz, 3 H, CH₃); ¹³ C NMR (CDCl₃) δ174.15, 152.96, 136.44, 130.64, 128.05, 122.06, 86.28, 60.59, 33.28,30.54, 24.68, 14.24; IR (neat) 3373 (OH), 2980, 2957, 1707 (C=O), 1445cm ⁻¹. HRMS m/z calculated for C₁₂ H₁₅ O₃ I 334.00660, found 334.00617.

EXAMPLE 8 Preparation of Compound 9

To a dried flask was added Pd(PPh₃)₄ (18 mg, 0.016 mmol). To this wasadded compound 8 (264 mg, 0.79 mmol) in 2 ml of THF, and the reactionmixture was stirred in an ice-water bath. Cyclopentadiene monoepoxide(97 mg, 1.18 mmol) in 2 ml of THF was added dropwise at 0° C, andstirring was continued for 20 min. at this temperature and another 24hr. at room temperature. The reaction mixture was concentrated. Theresidue was purified by flash chromatography with 2:1 hexane/EtOAc togive product 9: 235 mg, 71% yield; R_(f) =0.27 (2:1 hexane EtOAc); ¹ HNMR (CDCl₃) δ 7.58 (dd, J=7.8 and 1.5 Hz, 1 H, Ar), 7.15 (dd, J=7.8 and1.5 Hz, 1 H, Ar), 6.77 (t, J=7.8 Hz, 1 H, Ar), 6.09 (m, 1 H, HC=C), 6.01(m, 1 H, HC=C), 5.11 (m, 1 H, CHOAr), 4.68 (m, 1 H, CHOH), 4.12 (q,J=7.2 Hz, 2 H, OCH₂), 2.85 (m, 2 H), 2.60 (ddd, J=15.3 and 9.6 and 6.0Hz, 1 H, CH₂ in cyclopentane), 2.30 (dt, J=1.8 and 6.9 Hz, 2 H), 2.06(dt, J=14.7 and 3.9 Hz, 1 H, CH₂ in cyclopentane), 1.88 (m, 2 H), 1.25(t, J=6.3 Hz, 3 H, CH₃), 0.88 (m, 1 H, OH); ¹³ C NMR (CDCl₃) δ 173.69,156.22, 138.09, 137.98, 136.65, 133.55, 130.56, 125.87, 92.45, 85.71,74.97, 60.52, 41.28, 33.50, 30.86, 25.47, 14.28; IR (neat) 3350 (OH,2959, 1720 (C=O), 1599, 1462, 1352 cm⁻¹ ; HRMS m/z calculated for C₁₇H₂₁ O₄ I 416.04847, found 416.04747.

EXAMPLE 9 Preparation of Compound 16

In a vial were placed compound 9 (94 mg, 0.23 mmol), 1-octen-3-one (285mg, 2.3 mmol), n-Bu₄ NCl (Lancaster, 70 mg, 0.25 mmol), i-Pr₂ NEt (98μL, 0.58 mmol), Pd(OAc)₂ (2.5 mg, 0.011 mmol) and DMF (0.46 ml). Afterthe reaction was stirred for 12 hr. at 50° C., it was poured into 40 mlof EtOAc. The mixture was washed with saturated NH₄ Cl (15 ml) and thenthe aqueous phase was back-extracted with EtOAc (15 ml). The overallorganic phase was washed with brine (15 ml), and then dried over MgSO₄and concentrated under reduced pressure. The residue was purified byflash chromatography to give product 16: 37 mg, 42% yield; R_(f) =0.44(1:1 hexane/EtOAc); ¹ H NMR (CDCl₃) δ 6.94 (d, J=7.5 Hz, 1 H, Ar), 6.88(d, J=7.5 Hz, 1 H, Ar), 6.85 (dd, J=15.9 and 9.9 Hz, 1 H, C=CH), 6.75(t, J=7.5 Hz, 1 H, Ar), 6.21 (d, J=19.5 Hz, 1 H, HC=C), 5.39 (dd, J=8.1and 6.0 Hz, 1 H, CHOAr), 4.30 (m, 1 H, CHOH), 4.12 (m, 2 H), 3.99 (t,J=8.4 Hz, 1 H), 2.85 (dt, J=3.9 and 9.6 Hz, 1 H), 2.55 (m, 4 H), 2.26(m, 2 H), 2.18 (ddd, J=15.3 and 6.0 and 4.5 Hz, 1 H, CH₂ incyclopentane), 2.02 (m, 2 H), 1.88 (m, 1 H), 1.63 (m, 2 H), 1.28 (m, 7H, CH₂ 's and OCH₂ CH₃), 0.89 (t, J=6.9 Hz, 3 H, CH₃); ¹³ C NMR (CDCl₃)δ 200.94, 173.79, 157.68, 144.27, 132.17, 129.05, 127.05, 123.61,123.20, 120.06, 88.92, 76.69, 60.26, 52.63, 50.69, 43.01, 38.94, 33.36,31.46, 28.94, 24.81, 24.00, 22.42, 14.22, 13.90; IR (neat) 3464 (OH),2932, 1732 (C=O), 1688 (C=O), 1465 cm⁻¹ ; HRMS m/z calculated for C₂₅H₃₄ O₅ 414.24063, found 414.24118.

EXAMPLE 10 Preparation of Compounds 17 (R=Et) and 18 (R=Et)

To a solution of LiAlH₄ (Aldrich, 2.8 ml, 0.539 M in THF, 1.52 mmol) wasadded ethanol (0.76 ml, 2 M in THF, 1.52 mmol) dropwise over 10 min. atroom temperature. Subsequently, a THF solution of (S)-binaphthol(Aldrich, 429 mg, 1.52 mmol in 2.4 ml of THF) was added dropwise, andthe resulting mixture was stirred for 30 min. Enone 16 (199 mg, 0.51mmol) in 2 ml of THF was added dropwise over 3 min. at -100° C., andstirring was continued for 2 hr at -100° C. and for another 2 hr at -78°C. The reaction was quenched by adding methanol (0.5 ml) at -78° C. andwarmed to room temperature. After addition of water (0.5 ml) and ether(15 ml), stirring was continued for an additional 30 min. To thismixture was added anhydrous MgSO₄ and the mixture was filtered throughCelite. Concentration, followed by flash chromatography with 1:2hexane/EtOAc, gave compounds 17 (R=Et, 49 mg, 25% yield) and 18 (R=Et,50 mg, 25% yield).

Compound 17 (R=Et): R_(f) =0.25 (1:2 hexane/-EtOAc); ¹ H NMR (CDCl₃) δ6.91 (d, J=7.5 Hz, 2 H, Ar), 6.73 (t, J=7.5 Hz, 1 H, Ar), 5.66 (m, 2 H,HC=CH), 5.33 (t, J=7.8 Hz, 1 H, CHOAr), 4.20 (m, 1 H, CHOH), 4.10 (m, 3H, OCH₂ and C=CHCHOH), 3.87 (t, J=8.7 Hz, CHAr), 2.74 (m, 1 H), 2.64(dd, J=12.9 and 6.6 Hz, 1 H), 2.55 (dt, J=21.3 and 7.2 Hz, 1 H), 2.38(d, J=15.0 Hz, 1 H, CH₂ in cyclopentane), 2.27 (dt, J=2.1 and 1.8 Hz, 1H), 2.15 (ddd, J=15.0 and 6.0 and 4.5 Hz, 1 H, CH₂ in cyclopentane),2.04-1.78 (m, 4 H), 1.67 (br s, 2 H, OH's), 1.54 (m, 1 H), 1.33 (m, 6H), 1.25 (t, J=7.5 Hz, 3 H, CH₃), 0.92 (t, J=6.3 Hz, CH₃); ¹³ C NMR(CDCl₃) δ 173.90, 157.81, 136.44, 128.73, 128.15, 127.76, 123.91,122.99, 119.82, 88.28, 76.93, 72.96, 60.30, 52.28, 50.04, 42.37, 37.04,33.52, 31.81, 29.06, 25.25, 24.89, 22.69, 14.29, 14.10; IR (neat) 3486(OH), 1732 (C=O) cm⁻¹ ; HRMS m/z calculated for C₂₅ H₃₆ O₅ 416.25628,found 416.25541.

Compound 18 (R=Et): R_(f) =0.48 (1:2 hexane/-EtOAc); ¹ H NMR (CDCl₃) δ6.97 (d, J=7.2 Hz, 1 H, Ar), 6.92 (d, J=7.5 Hz, 1 H, Ar), 6.74 (t, J=7.5Hz, 1 H, Ar), 5.71 (m, 2 H, HC=CH), 5.34 (t, J=6.9 Hz, 1 H, CHOAr), 4.19(m, 1 H, CHOH), 4.11 (m, 3 H, OCH₂ and C═CHCHOH), 3.90 (t, J=11.7 Hz, 1H, CHAr), 2.75 (m, 1 H), 2.59 (m, 1 H), 2 38 (d, J=15.0 Hz, 1 H, CH₂ incyclopentane), 2.27 (m, 2 H), 2.16 (ddd, J=15.0 and 6.0 and 4.5 Hz, 1 H,CH₂ in cyclopentane), 2.05- 1.82 (m, 4 H), 1.72 (d, J=6.0 Hz, 1 H), 1.53(br s, 2 H, OH's), 1.29 (m, 6 H), 1.25 (t, J=7.5 Hz, 3 H, CH₃), 0,88 (m,3 H, CH₃); ¹³ C NMR (CDCl₃) δ 173.87, 157.69, 136.34, 128.70, 127.76,127.08, 124.04, 122.95, 119.85, 88.23. 77.02, 72.53, 60.27, 52.38,50.06, 42.52, 37.27, 33.49, 31.80, 29.04, 25.19, 24.86, 22.63, 14.27,14.10; IR (neat) 3416 (OH), 3053, 2845, 1732 (C═O), 1599, 1447 cm⁻¹ ;HRMS m/z calculated for C₂₅ H₃₆ O₅ 416.25628, found 416.25711.

EXAMPLE 11 Preparation of Compounds 17 (R=Et) and 19 (R=Et)

In a vial were placed compound 9 (109 mg, 0.26 mmol), γ-stannyl alcohol14 (164 mg, 0.39 mmol), i-Pr₂ NEt (85 mg, 0.66 mmol), n-Bu₄ NCl(Lancaster, 88 mg, 0.31 mmol), Pd(OAc)₂ (2.9 mg, 0.013 mmol) and DMF(0.52 ml) as a solvent. After the resulting mixture was stirred for 12hr. at room temperature, it was passed through a silica gel pad with 1:2hexane/EtOAc. The solution was concentrated, and the residue waspurified by flash chromatography with 1:2 hexane/EtOAc to give compounds17 (R=Et, 15 mg, 14% yield) and 19 (R=Et, 17 mg, 16% yield). Thespectral data for compound 19 are the same as those of compound 18(R=Et).

EXAMPLE 12 Preparation of 12-epi-5,6,7-trinor-4,8-inter-m-phenylene PGI₂[17 (R=H)].

To a solution of compound 17 (R=Et, 22 mg, 0.06 mmol) in 0.74 ml of THFwas added 3 N aqueous NaOH (0.37 ml) at room temperature. After themixture was stirred for 6 days at room temperature, it was neutralizedby 2 N aqueous HCl. The organic phase was decanted with EtOAc, and thendried over MgSO₄. Concentration, followed by flash chromatography with20:1 EtOAc/MeOH, gave product 17 (R=H): 17 mg, 83% yield; R_(f) =0.29(20:1 EtOAc/MeOH); ¹ H NMR (CDCl₃) δ 6.90 (d, J=7.5 Hz, 1 H, Ar), 6.89(d, J=7.5 Hz, 1 H, Ar), 6.72 (t, J=7.5 Hz, 1 H, Ar), 5.61 (m, 2 H,HC=CH), 5.31 (dd, J=0.9 and 7.8 Hz, 1 H, CHOAr), 4.30 (br s, 2 H, OH's),4.18 (m, 1 H, CHOH), 4.03 (m, 1 H, C═CCHOH), 3.85 (t, J=9.0 Hz, 1 H,CHAr), 2.75-2.65 (m, 2 H), 2.53 (m, 1 H), 2.36 (d, J=15.0 Hz, 1 H, CH₂in cyclopentane), 2.26 (m, 2 H), 2.17-2.01 (m, 2 H), 1.81 (m, 1 H), 1.53(m, 3 H), 1.32 (m, 6 H), 0.91 (t, J=6.9 Hz, 3 H, CH₃) ¹³ C NMR (CDCl₃) δ177.93, 157.99, 136.35, 128.91, 128.29, 127.65, 123.97, 122.80, 119.98,88.37, 77.00, 73.04, 52.18, 49.95, 42.02, 36.96, 32.89, 31.83, 28.83,25.28, 24.85, 22.73, 14.12; IR (neat) 3383 (OH), 2928, 1709 (C═O), 1595,1454 cm⁻¹ ; HRMS m/z calculated for C₂₃ H₃₂ O₅ 388.22497, found388.22406. Anal. Calcd for C₂₃ H₃₂ O₅ : C, 71.11; H, 8.30. Found: 70.75;H, 8.92.

EXAMPLE 13 Preparation of 12,15-epi-5,6,7-trinor-4,8-inter-m-phenylenePGI₂ [18 (R=H)].

To a solution of compound 18 (R=Et, 55 mg, 0.14 mmol) in 1.8 ml of THFwas added 3 N aqueous NaOH (0.9 ml) at room temperature. After thereaction was stirred for 6 days at room temperature, it was neutralizedby 2 N aqueous HCl. The organic phase was decanted with ethyl acetateand dried over MgSO₄. Concentration in vacuo followed by flashchromatography with 20:1 EtOAc/MeOH gave compound 18 (R=H): 47 mg, 92%yield; R_(f) =0.37 (20:1 EtOAc/MeOH); ¹ H NMR (CDCl₂) δ 6.94 (d, J=7.5Hz, 1 H, Ar), 6.90 (d, J=7.5 Hz, 1 H, Ar), 6.74 (t, J=7.5 Hz, 1 H, Ar),5.72 (dd, J=15.3 and 5.1 Hz, 1 H, HC=C), 5.65 (dd, J=15.3 and 7.8 Hz, 1H, C=CH), 5.62 (br s, 2 H, OH's), 5.32 (t, J=6.9 Hz, 1 H, CHOAr), 4.20(m, 1 H, CHOH), 4.12 (dd, J=12.0 and 9.0 Hz, 1 H, C═CHCHOH), 3.89 (t,J=8.7 Hz, 1 H), 2.80 (dt, J=4.2 and 9.0 Hz, 1 H), 2.70 (m, 1 H), 2.54(m, 1 H), 2.38 (d, J=15.9 Hz, 1 H, CH₂ in cyclopentane), 2.29 (dd,J=14.1 and 6.3 Hz, 2 H), 2.22-2.04 (m, 2 H), 1.84 (m, 1 H), 1.49 (m, 3H), 1.29 (m, 6 H), 0.89 (t, J=6.3 Hz, 3 H, CH₃); ¹³ C NMR (CDCl₃) δ178.54, 157.87, 136.26, 128.88, 127.64, 126.73, 124.15, 122.72, 119.92,88.00, 76.93, 72.39, 52.27, 49.92, 42.12, 37.19 33.07, 31.81, 28.97,25.17, 24.64, 22.64, 14.13; IR (neat) 3412 (OH), 3271 (OH), 3063, 2924,2858, 1709 (C═O), 1456, 1254 cm⁻¹ ; HRMS m/z calculated for C₂₃ H₃₂ O₅388.22497, found 388.22589. Anal. Calcd for C₂₃ H₃₂ O₅ ; C, 71.11; H,8.30. Found: C, 70.36, H, 8.09.

All patents, patent documents and publications cited herein areincorporated by reference herein, as though fully set forth.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A method for preparing benzoprostacyclinscomprising reacting a compound of the general formula (III): ##STR9##wherein R¹ is a pharmaceutically-acceptable cation, H or (C₁ -C₁₂)alkyl;A is --CH₂ --, --O--CH₂ --, CH₂ --CH₂ -- or --CH═CH--; and R² is H, (C₁-C₁₂)alkyl, (C₂ -C₁₀)acyl or (C₇ -C₁₃)aroyl with a molar excess compoundof a general formula (IV):

    R.sup.7 --CH═CH--C(R.sup.8)(R.sup.9)--CH(R.sup.4)--B--R.sup.5 (IV)

wherein R⁵ is (C₁ -C₅)alkyl; B is --(CH₂)_(n) --Z wherein n is 0-4 and Zis --CH₂ CH₂ --, --CH═CH-- or --C.tbd.C--; R⁴ is H, F, CH₃ or CH₂ CH₃ ;and R⁷ is ((C₁ -C₄)alkyl)₃ Sn, (phenyl)₃ Sn or H; R⁸ is H or (C₁-C₁₂)alkyl; and R⁹ is OR³, wherein R³ is H, (C₁ -C₁₂)alkyl, (C₂-C₁₀)acyl or (C₇ -C₁₃)aroyl, or R⁸ and R⁹ taken together are keto;wherein the reaction is carried out at about 20°-75° C. for about 5-48hrs in an organic solvent in the presence of a catalytic amount ofPd(O), and an organic amine to yield a compound of the formula (II):##STR10## wherein R¹, A, R², R⁸, R⁹, R⁴, B and R⁵ are as defined above.2. The method of claim 1, wherein R⁸ and R⁹ taken together are keto incompound II, further comprising reducing the C₁₅ -keto group of compoundII with a reducing agent to yield a compound of formula II wherein R⁸ isH and R⁹ is OH.
 3. The method of claim 1 wherein R⁷ is (n-butyl)₃ Sn, R⁸is H and R⁹ is OH.
 4. The method of claim 1, wherein compound IIcomprises (S)C₁₅ --OH.
 5. The method of claim 4 wherein the C₁₁ --OR²bond is in the alpha-configuration.
 6. The method of claim 1 wherein, incompound III, R¹ is (C₁ -C₁₂)alkyl and R² is H.
 7. The method of claim6, further comprising saponifying the CO₂ R¹ moiety of compound II toyield CO₂ H.
 8. The method of claim 7, further comprising forming apharmaceutically-acceptable alkali metal salt, ammonium, or amine saltof the moiety CO₂ H.
 9. The method of claim 1 wherein the Pd(O) isformed in situ from a Pd(II) compound.
 10. The method of claim 9 whereinthe Pd(II) compound is Pd(OAc)₂.
 11. The method of claim 1 wherein theorganic base comprises a tri(C₂ -C₁₂)alkylamine.
 12. The method of claim11 wherein the organic amine comprises diisopropyl(ethyl)amine.
 13. Themethod of claim 1 wherein the mole ratio of III:IV is about 1:1.25-20.14. The method of claim 6 wherein A is --CH₂ -- or --CH₂ --CH₂ -- and Bis CH₂ --CH₂ --CH₂.
 15. The method of claim 14 wherein R⁴ is H and R⁵ isCH₃.